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Arsenic directly stimulates the kinase Hog1 to promote the gene expression required for arsenic detoxification in yeast. Hog1 directly senses arsenic The mitogen-activated protein kinase (MAPK) Hog1 mediates the response of yeast cells to various stressors, including osmotic shock, heat shock, and arsenic. The arsenic-binding transcription factor Yap8 stimulates the expression of genes required for arsenic detoxification. Guerra-Moreno et al. found that arsenic bound directly to Hog1 through three conserved cysteine residues that were required for growth in the presence of arsenic but not for the response to osmotic stress. Arsenic binding to Hog1 promoted the phosphorylation and nuclear localization of Yap8 and enhanced the expression of Yap8 target genes. Thus, Hog1 directly senses arsenic to enhance Yap8-mediated arsenic detoxification. Some human MAPKs bound to arsenic in vitro, suggesting that arsenic binding by this family of kinases may be evolutionarily conserved. The yeast stress-activated protein kinase Hog1 is best known for its role in mediating the response to osmotic stress, but it is also activated by various mechanistically distinct environmental stressors, including heat shock, endoplasmic reticulum stress, and arsenic. In the osmotic stress response, the signal is sensed upstream and relayed to Hog1 through a kinase cascade. Here, we identified a mode of Hog1 function whereby Hog1 senses arsenic through a direct physical interaction that requires three conserved cysteine residues located adjacent to the catalytic loop. These residues were essential for Hog1-mediated protection against arsenic, were dispensable for the response to osmotic stress, and promoted the nuclear localization of Hog1 upon exposure of cells to arsenic. Hog1 promoted arsenic detoxification by stimulating phosphorylation of the transcription factor Yap8, promoting Yap8 nuclear localization, and stimulating the transcription of the only known Yap8 targets, ARR2 and ARR3, both of which encode proteins that promote arsenic efflux. The related human kinases ERK1 and ERK2 also bound to arsenic in vitro, suggesting that this may be a conserved feature of some members of the mitogen-activated protein kinase (MAPK) family. These data provide a mechanistic basis for understanding how stress-activated kinases can sense distinct threats and perform highly specific adaptive responses.